KR100226386B1 - Direct compression method for preparing pills having cephalosporanic acid derivatives - Google Patents
Direct compression method for preparing pills having cephalosporanic acid derivatives Download PDFInfo
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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Abstract
Description
본 발명은 세팔로스포린을 기재로 한 새로운 제약학적 형태에 관한 것이다. 이는 특히 신규의 정제화된 제약학적 형태에 관한 것이다.The present invention relates to novel pharmaceutical forms based on cephalosporins. This relates in particular to novel tableted pharmaceutical forms.
본 발명은 경구 투여할 수 있는 7-아실아미노세팔로스포란산의 반합성 유도체를 기재로 한 새로운 정제화된 제약학적 형태에 관한 것이다. 그것은 바람직하게, 7-아실아미노-3-비닐세팔로스포란산의 유도체에 관한 것이다. 그것은 특히 (6R, 7R)-7-[(Z)-2-(2-아미노-4-티아졸릴)-2-카르보메톡시이미노아세트아미도]-8-옥소-3-비닐-5-티아-1-아자-2-비시클로-[4. 2. 0]옥텐-2-카르복실산의 형성에 관한 것이다. 이러한 세팔로스포린은 세피자임(Cefixime)이라는 국제 일반 명칭으로 더 잘 알려져 있다.The present invention relates to novel tableted pharmaceutical forms based on semisynthetic derivatives of 7-acylaminocephalosporranic acid that can be administered orally. It preferably relates to derivatives of 7-acylamino-3-vinylcephalosporanic acid. It is especially (6R, 7R) -7-[(Z) -2- (2-amino-4-thiazolyl) -2-carbomethoxyiminoacetamido] -8-oxo-3-vinyl-5- Thia-1-aza-2-bicyclo- [4. 2. 0] Octene-2-carboxylic acid. This cephalosporin is better known by the international generic name Cefixime.
세팔로스포린류의 화합물들은 높은 항생물질 활성을 나타내지만; 그들의 이용은 다른 항생 요법이 만족스럽지 못하다고 판명되는 비교적 심각한 경우를 위하여 보류되는 것이다. 그들의 매우 높은 활성을 인하여, 이들 화합물은 몇몇 나라에서 그들의 생산에 관하여 매우 엄격한 법률을 제정하게 한다. 따라서, 이러한 종류의 화합물은 단지 특정 공간에서만 제조되고 제형화 될 수 있는데, 이는 임의의 다른 약물과의 임의의 상호 오염을 방지하기 위해서이다.Compounds of cephalosporins exhibit high antibiotic activity; Their use is reserved for relatively serious cases where other antibiotic therapies turn out to be unsatisfactory. Because of their very high activity, these compounds allow some countries to enact very strict laws regarding their production. Thus, compounds of this kind can only be prepared and formulated in certain spaces in order to prevent any cross contamination with any other drug.
상기 활성 물질의 성평에 또다른 어려움은 그 비용에 의한 것이다. 실제로 이러한 생성물은 많은 합성 단계를 요하는 긴 공정에 의해 얻어지고, 따라서 구입시 극히 높은 재료 비용으로서 공급된다.Another difficulty with the evaluation of the active substance is its cost. Indeed such products are obtained by long processes that require many synthetic steps and are therefore supplied at extremely high material costs at the time of purchase.
그러므로 상기 언급된 두가지 이유로 인하여 가능한 한 생성물 손실을 피하는 가공 기술을 갖는 것이 필요하다.It is therefore necessary to have a processing technique that avoids product loss as much as possible for the two reasons mentioned above.
정제로의 제약학적 성형 기술을 언급함에 있어서, 두가지 제조 경로가 공지되어 있다:In referring to the pharmaceutical molding technique into tablets, two preparation routes are known:
- 습윤 경로에 의한 성형Molding by Wet Path
- 직접 압축에 의한 성형-Forming by direct compression
첫번째의 경우, 즉 습윤 경로에 의해 활성 물질을 성형하는 경우, 하기 일련의 단계들에 직면하게 된다:In the first case, i.e., shaping the active material by the wet route, the following sequence of steps is encountered:
- 활성 물질 및 부형제의 계량-Metering of active substances and excipients
- 최종 제제의 다양한 성분들의 덩어리 해체 및 선별Clumping and screening of various components of the final formulation
- 활성 물질 및 부형제의 일차 혼합 및 얻어진 혼합물의 균질성 검사-Primary mixing of the active substance and excipients and homogeneity examination of the resulting mixture
- 혼합물의 침윤Infiltration of the mixture
- 과립화Granulation
- 건조- dry
- 입자의 분쇄-Grinding of particles
- 희석-Dilution
- 최종혼합-Final mixing
- 압축-Compression
상기 일련의 단계들은 8가지 상이한 유형의 장치의 존재를 필요로 한다. 활성 물질의 독성으로 인하여, 전체 성형 작업은 상기 장비 각각에 있어서 오염 없는 세척을 필요로 한다. 손실분이 2% 미만의 값으로 감소될 수 없으므로, 장비의 교체는 한편으로는 생산 비용을 크게 증가시키고, 다른 한편으로는 공정의 임의의 자동화를 방해한다. 환경보호 및 산업 위생은 합성 단계의 수 및 장비의 부품수가 많을수록, 이에 비례하여 조절하기가 더 어렵다, 더욱이, 습윤 경로 공정은 도저히 무시할 수 있는 성질이 아닌 생성물의 열화의 위험을 수반하는 건조를 필요로 한다. 이러한 모든 기술적 제한과 환경에 대한 법적 제한은 생산업자가 습윤 경로에 의한 성형을 포기하도록 한다.The series of steps requires the presence of eight different types of devices. Due to the toxicity of the active substance, the entire molding operation requires a pollution free cleaning of each of the above equipments. Since losses cannot be reduced to less than 2%, the replacement of equipment greatly increases production costs on the one hand and on the other hand hinders any automation of the process. Environmental protection and occupational hygiene are more difficult to control in proportion to the number of synthesis stages and the number of parts of the equipment. Moreover, the wet route process requires drying, which is not negligible in nature and involves the risk of degradation of the product. Shall be. All these technical limitations and legal restrictions on the environment allow producers to abandon molding by the wet route.
활성 성분 정제의 제약학적 형태 제조를 위한 두번째의 가능한 경로는 분말 혼합물의 직접 압축을 수행하는 것으로 구성되며, 본 발명의 경우 혼합물은 세팔로스포린 및 부형제로 구성된다.The second possible route for the preparation of the pharmaceutical form of the active ingredient tablet consists of performing a direct compression of the powder mixture, in which case the mixture consists of cephalosporins and excipients.
상기 기술은 또한, 부형제에 비하여 높은 비율의 활성 성분이라는 관점으로 부터, 본 발명의 영역 밖에 있는 것으로 보였다. 알반적으로 직접 압축공정은 활성 물질의 양이 100㎎ 미만이고 정제 내 활성 물질의 비율이 25%를 초과하지 않는 정제에 사용한다. 상기 퍼센트 이상에서는 부형제의 덩어리 내에 활성 물질을 묻는 것이 불가능하므로, 활성 물질 상의 물리적 및 화학적 제한들로 부터 자유로울 수가 없다.The technique also appears to be outside the scope of the present invention from the standpoint of high proportion of active ingredient relative to excipients. Usually direct compression is used for tablets in which the amount of active substance is less than 100 mg and the proportion of active substance in the tablet does not exceed 25%. Above this percentage it is impossible to bury the active substance in the mass of excipients and therefore cannot be free from physical and chemical limitations on the active substance.
매우 놀랍게도, 본 발명의 영역 내에서 상기 모든 문제를 20 내지 90% 및 바람직하게 30 내지 70% 범위인 정제 내 활성 물질의 중량 비율로서 세팔로스포린 및 하나 이상의 부형제들을 포함하는 혼합물의 직접 압축을 수행하므로써 해결할 수 있음을 발견하였다.Very surprisingly, within the scope of the present invention all of the above problems are carried out by direct compression of a mixture comprising cephalosporin and one or more excipients as the weight ratio of active substance in the tablet, which ranges from 20 to 90% and preferably 30 to 70% We found that this can be solved.
본 발명에서 사용되는 세팔로스포린은 바람직하게 7-아실아미노-3-비닐세팔로스포란산의 유도체이고, 가장 특별하게는 상기 유도체는 세파자임이라는 명칭 하에 판매되는 것이다.The cephalosporins used in the present invention are preferably derivatives of 7-acylamino-3-vinyl cephalosporranic acid, most particularly the derivatives being sold under the name Sephazyme.
사용되는 부형제는 특히 하기로 부터 선택한다:The excipients used are especially chosen from:
- 탄산칼슘Calcium Carbonate
- 인산칼슘Calcium phosphate
- 황산칼슘Calcium sulfate
- 미소 결정 셀룰로오스-Microcrystalline cellulose
- 셀룰로오스 분말-Cellulose powder
- 과당-Fructose
- 다양한 형태의 유당-Lactose in various forms
- 만니톨-Mannitol
- 소르비톨-Sorbitol
- 전분-Starch
- 예비 겔화된 전분Pregelatinized starch
- 당- Party
또한, 마그네슘 스테아레이트, 스테아르산, 활석 또는 폴리에틸렌 글리콜과 같은 윤활제를 첨가할 수 있다.In addition, lubricants such as magnesium stearate, stearic acid, talc or polyethylene glycol can be added.
본 발명의 건조 경로에 의한 압축을 이행하는데 바람직한 활성 물질의 입자 크기 분포는 하기와 같다:Preferred particle size distributions of the active materials for effecting compaction by the drying route of the present invention are as follows:
- 250㎛ 이상의 직경을 갖는 입자 5% 미만Less than 5% of particles having a diameter of at least 250 μm
- 250 내지 90㎛ 사이의 직경을 가지는 입자 95%95% of particles having a diameter between 250 and 90 μm
- 90㎛ 이하의 직경을 가지는 입자 5 내지 40%5-40% of particles having a diameter of 90 μm or less
활성 물질의 상대 밀도는 바람직하게 0.6 내지 0.9이다.The relative density of the active material is preferably 0.6 to 0.9.
제조 공정은, 다양한 성분들을 계량하고, 그들을 덩어리 해체하고 윤활제를 제외한 모든 성분을 첫번째 혼합시키며, 그 후 윤활제를 첨가하고, 최종혼합을 수행하고, 그리고 압축을 수행하는 것으로 구성된다. 상기 공정은 단지 4개 부품의 장비를 사용하는데, 이는 활성 물질의 손실을 1% 이하로 감소시키는 이점을 가진다.The manufacturing process consists of weighing the various components, disaggregating them and first mixing all the components except the lubricant, then adding the lubricant, performing the final mixing, and performing the compression. The process uses only four parts of equipment, which has the advantage of reducing the loss of active material to less than 1%.
또한 본 발명의 일부를 형성하는 상기 서술된 공정에 의해 얻어진 정제는 습윤경로 압축에 의해 제조된 동일한 정제보다 더 우수한 취쇄성(脆碎性) 및 분열기준을 나타낸다. 그들은 활성 물질의 탁월한 분포의 균일성을 나타낸다.The tablets obtained by the above-described processes forming part of the present invention also exhibit better brittleness and cleavage criteria than the same tablets produced by wet path compression. They exhibit an excellent uniformity of the distribution of active substances.
본 발명을 제한하는 것으로 간주되어서는 아니되는 하기 실시예들에 의하여, 본원 발명은 보다 완전히 서술될 것이다.The invention will be more fully described by the following examples which should not be considered as limiting the invention.
하기 물질들을 사용한다:Use the following materials:
세피자임 삼수화물 184.60㎏Sepyzyme trihydrate 184.60㎏
예비 겔화된 전분(전분 1500) 48.98㎏48.98 kg pregelatinized starch (starch 1500)
인산이칼슘 이수화물 122.44㎏Dicalcium Phosphate Dihydrate 122.44㎏
마그네슘 스테아레이트 2.03㎏Magnesium Stearate 2.03㎏
미소 결정 셀룰로오스(아비셀 PH 102) 41.95㎏41.95 kg of microcrystalline cellulose (avicel PH 102)
세피자임 삼수화물은 하기의 입자크기 분포를 갖는다:Sepizyme trihydrate has the following particle size distribution:
μ 단위의 스크린 크기 퍼센트Screen size percent in μ
1400 01400 0
1000 0.141000 0.14
710 0.23710 0.23
500 0.33500 0.33
355 0.42355 0.42
250 1.6250 1.6
180 4.13180 4.13
125 37.11125 37.11
90 39.1690 39.16
찌꺼기 16.85Residue 16.85
다양한 물질들, 활성 물질 및 부형제를 1-mm 메시를 갖는 스크린을 통과시켜 덩어리 해체 작업을 수행했다. 물질들을 계량하고-마그네슘 스테아레이트를 제외하고- 1,000리터 혼합기에 채웠다. 10rpm(분당 회전 속도)의 속도로 10분 동안 혼합을 수행했다. 사전에 0.680-mm 스크린 상에서 덩어리 해체된 마그네슘 스테아레이트를 첨가했다. 다시 5분 동안 혼합을 수행했다. 압축을 위해 43의 위치 번호를 갖는 페트(Fette) P 2000 프레스를 사용한다. 시간당 200,000개의 정제를 생산했다. 제조된 정제의 중량 397㎏이고, 99.2%의 생산 효율을 나타냈다. 정제는 프랑스 약전에 의하면 산포분과 함께 491.5mg의 평균 중량을 갖는다. 15개 정제에 대해 수행된 세피자임의 측정치는 192.7mg 내지 200.8mg으로 다양하다.Agglomeration dissolution was carried out by passing various materials, active materials and excipients through a screen with a 1-mm mesh. The materials were weighed-except for magnesium stearate-and filled into a 1000 liter mixer. Mixing was performed for 10 minutes at a speed of 10 rpm (rotation speed per minute). Agglomerated magnesium stearate was added beforehand on a 0.680-mm screen. Again mixing was performed for 5 minutes. A Fett P 2000 press with a position number of 43 is used for compression. Produced 200,000 tablets per hour. The tablet produced was 397 kg in weight and exhibited a production efficiency of 99.2%. The tablet has an average weight of 491.5 mg with scattered powder according to the French Pharmacopoeia. The measurement of cepizyme performed on 15 tablets varied from 192.7 mg to 200.8 mg.
정제의 경도는 슐레우니저(Schleuniger) 4M 형의 장치 상에서 통상적인 방법으로 20개 정제에 대해 측정했고, 측정치는 10 내지 14 킬로 중량이다.The hardness of the tablets was measured for 20 tablets in a conventional manner on a Schleuniger 4M type apparatus, with measurements of 10 to 14 kilo weights.
또한 상부 및 하부 펀치의 변형 및 압축 기계의 매트릭스에서의 상부펀치의 움직임을 측정하는 한 세트의 센서들을 사용하여, 신장계(extensometry)라인 상에서 상부 펀치에 적용된 힘(킬로뉴튼으로 표시)의 함수로서 혼합물의 압축성을 측정했다. 혼합물의 압축성을 나타내는 비교 곡선을 작성했다. 이들 곡선은, 상부 펀치에 적용된 뉴튼 단위의 힘의 함수로서, 슐레우니저 장치 내 정제의 경도의 측정으로 부터 유래한다. 이 힘은 변형 게이지로써 측정한다. 비교용 신장계 곡선을 습윤 압축 및 직접 압축에 의해 얻어진 정제들에 대해 작성했다(참고 제 1 도). 얻어진 곡선은 간단한 혼합이 압축에 대해 더 우수한 반응을 제공함을 보인다. 직접 압축에 의해 얻어진 정제는 습윤 입도 측정에 의해 얻어진 것들 보다 현저히 높은 경도를 나타낸다. 10분 후 20회전/분에서 엘베카(Erweka) 모델 TAB 장치 상에서 측정한 20개 정제의 취쇄성은 0.1%이다.The mixture is also a function of the force (expressed in kilonewtons) applied to the upper punch on an extensometry line, using a set of sensors that measure the deformation of the upper and lower punches and the movement of the upper punch in the matrix of the compression machine. The compressibility of was measured. A comparative curve showing the compressibility of the mixture was created. These curves derive from the measurement of the hardness of the tablets in the Schlenizer device as a function of the force in Newton units applied to the upper punch. This force is measured with a strain gauge. Comparative extensometer curves were prepared for tablets obtained by wet compression and direct compression (Reference FIG. 1). The curve obtained shows that simple mixing provides a better response to compression. Tablets obtained by direct compression show significantly higher hardness than those obtained by wet particle size measurements. The brittleness of the 20 tablets measured on an Erweka model TAB apparatus at 20 revolutions / minute after 10 minutes is 0.1%.
또한, 산업 역사는 다양한 직접 압축 배치들(batches)들로 부터 생성된 정제의 생약 특성(경도, 취쇄성, 분열도, 용해도)의 일관성을 보여준다.In addition, industry history shows the consistency of the herbal properties (hardness, brittleness, cleavage, solubility) of tablets produced from various direct compression batches.
[실시예 2]Example 2
하기 물질들을 사용한다:Use the following materials:
세피자임 삼수화물 46.666㎏Sepyzyme Trihydrate 46.666㎏
예비 겔화된 전분(전분 1500) 7.000㎏7.000 kg pregelatinized starch (starch 1500)
인산수소 칼슘 3.290㎏Calcium hydrogen phosphate 3.290㎏
미소 결정 셀룰로오스 12.624㎏Microcrystalline cellulose 12.624 kg
마그네슘 스테아레이트 0.420㎏Magnesium Stearate 0.420㎏
세파자임 삼수화물은 하기의 입자크기 분포를 갖는다.Sephazyme trihydrate has the following particle size distribution.
μ 단위의 스크린 크기 퍼센트Screen size percent in μ
1400 01400 0
1000 0.041000 0.04
710 0.03710 0.03
500 0.70500 0.70
355 1.06355 1.06
250 1.47250 1.47
180 4.52180 4.52
125 20.19125 20.19
90 56.1690 56.16
찌꺼기 14.83Residue 14.83
충전 후 상대 밀도 = 0.67Relative Density After Charging = 0.67
다양한 물질들, 활성 물질 및 부형제를 0.8mm의 메시 구멍을 갖는 격자 스크린을 통과시켜 덩어리 해체 작업을 수행했다. 상기 물질들을 계량하고(마그네슘 스테아레이트를 제외하고), 150리터 혼합기에 채웠다. 10rpm의 속도에서 10동안 혼합을 수행했다. 사전에 0.650mm 스크린 상에서 덩어리 해체한 마그네슘 스테아레이트를 첨가했다. 다시 혼합을 5분 동안 수행했다. 압축을 위해 24의 위치 번호를 갖는 코울토이(Courtoy) R 100 프레스를 사용했다. 시간당 110,000개의 정제가 생산됐다.Agglomeration dissolution was carried out by passing various materials, active materials and excipients through a grid screen with a mesh hole of 0.8 mm. The materials were weighed (except magnesium stearate) and charged to a 150 liter mixer. Mixing was carried out for 10 at a speed of 10 rpm. Agglomerated magnesium stearate was added beforehand on a 0.650 mm screen. Again mixing was performed for 5 minutes. A Coortoy R 100 press with a position number of 24 was used for compression. 110,000 tablets were produced per hour.
프랑스 약전에 따르면 정제는 산포분과 함께 596.3mg의 평균 중량을 갖는다. 20개 정제에 대해 수행된 세피자임 측정치는 394.4mg 내지 407.12mg으로 다양하다. 20개 정제에 대해 슐레우니저 장치로 측정한 정제의 경도는 10 내지 14kw로 다양하다.According to the French Pharmacopoeia, the tablets have an average weight of 596.3 mg with scattered powder. Sepizime measurements performed on 20 tablets varied from 394.4 mg to 407.12 mg. For 20 tablets the hardness of the tablets measured by the Schlenizer device varied from 10 to 14 kw.
[비교실시예 1]Comparative Example 1
하기 물질들을 사용한다:Use the following materials:
세피자임 삼수화물 106.620㎏Sepizyme Trihydrate 106.620㎏
예비 겔화된 전분(전분 1500) 6.750㎏6.750 kg pregelatinized starch (starch 1500)
인산이칼슘 이수화물 2.700㎏Dicalcium Phosphate Dihydrate 2.700㎏
미소 결정 셀룰로오스(아비셀 PH 120) 7.868㎏7.868 kg microcrystalline cellulose (avicel PH 120)
출발물질들을 계량하고 스키리닝한 다음, 400리터 혼합-조립기(granulator)내로 채웠다. 5분 동안 건조 혼합을 수행했다. 그 후 24kg의 물을 첨가한 다음 27%의 물을 함유하는 과립화된 덩어리를 얻을 때까지 물 8.32kg을 점차적으로 첨가했다. 과립화는 7분 걸렸다. 그 다음 과립을 유동 공기층 건조에서 1시간 15분동안 45℃의 공기 입구 온도 및 18℃-25℃의 출구 온도로 건조시켰다. 그후 얻어진 과립을 1mm의 메시크기를 갖는 스크린 위를 통과시켰다. 119.938kg의 과립을 얻었다.Starting materials were weighed and skinned and then filled into a 400 liter blender. Dry mixing was performed for 5 minutes. Then 24 kg of water were added and then 8.32 kg of water was gradually added until a granulated mass containing 27% of water was obtained. Granulation took 7 minutes. The granules were then dried at an air inlet temperature of 45 ° C. and an outlet temperature of 18 ° C.-25 ° C. for 1 hour and 15 minutes in flowing air bed drying. The granules obtained were then passed over a screen with a mesh size of 1 mm. 119.938 kg of granules were obtained.
그 다음 하기 것들을 계량한다:Then weigh the following:
미소 결정 셀룰로오스 14.394kgMicrocrystalline cellulose 14.394kg
예비 겔화된 전분 19.948kg19.948 kg pregelatinized starch
인산이칼슘 이수화물 63.838kgDicalcium Phosphate Dihydrate 63.838kg
마그네슘 스테아레이트 0.886kgMagnesium Stearate 0.886kg
앞서 얻어진 과립을 셀룰로오스, 전분 및 인산염과 혼합한 다음, 스테아레이트를 첨가하고 217.550kg의 최종 생성물을 얻었다. 이 혼합물은 페트 P 2000 프레스에서 압축한다. 215.38kg의 정제의 질량을 얻었고, 이는 사용된 질량을 기준으로 98%의 수율을 나타낸다. 정제는 490mg의 단위 중량을 갖고, 신장계 곡선은 제 1 도의 도표에 제시된다. 10분에 TAB 방법으로 측정한 정제의 취쇄성은 0.3%이다. 정제의 경도는 8.5 내지 9.5kw로 다양하다.The granules obtained previously were mixed with cellulose, starch and phosphate, then stearate was added and 217.550 kg of final product was obtained. This mixture is compressed in a PET P 2000 press. A mass of 215.38 kg tablets was obtained, which yields 98% yield based on the mass used. The tablet has a unit weight of 490 mg and the extensometer curve is shown in the diagram of FIG. The brittleness of the tablet measured by the TAB method at 10 minutes is 0.3%. Tablets vary in hardness from 8.5 to 9.5 kw.
Claims (6)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR9014210A FR2669221B1 (en) | 1990-11-15 | 1990-11-15 | PROCESS FOR THE PREPARATION BY DIRECT COMPRESSION OF TABLETS OF CEPHALOSPORANIC ACID DERIVATIVES. |
FR90/14210 | 1990-11-15 | ||
PCT/FR1991/000872 WO1992008463A1 (en) | 1990-11-15 | 1991-11-08 | Direct compression method for preparing pills having cephalosporanic acid derivatives |
Publications (2)
Publication Number | Publication Date |
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KR930702004A KR930702004A (en) | 1993-09-08 |
KR100226386B1 true KR100226386B1 (en) | 1999-10-15 |
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Application Number | Title | Priority Date | Filing Date |
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KR1019930701448A KR100226386B1 (en) | 1990-11-15 | 1991-11-08 | Direct compression method for preparing pills having cephalosporanic acid derivatives |
Country Status (11)
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US (1) | US5514383A (en) |
EP (1) | EP0557389B1 (en) |
JP (1) | JP3253074B2 (en) |
KR (1) | KR100226386B1 (en) |
AT (1) | ATE111734T1 (en) |
CA (1) | CA2094122C (en) |
DE (1) | DE69104220T2 (en) |
DK (1) | DK0557389T3 (en) |
ES (1) | ES2060417T3 (en) |
FR (1) | FR2669221B1 (en) |
WO (1) | WO1992008463A1 (en) |
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KR20030078105A (en) * | 2002-03-28 | 2003-10-08 | (주)다산메디켐 | The novel composition of excipient for solid dosage form |
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US5399356A (en) * | 1994-03-24 | 1995-03-21 | The Procter & Gamble Company | Process for making solid dose forms containing bismuth |
ES2079327B1 (en) * | 1994-12-13 | 1996-08-01 | Lilly Sa | PHARMACEUTICAL FORMULATIONS OF CEFACLOR. |
ATE199495T1 (en) * | 1994-12-14 | 2001-03-15 | Enbalt Trading Ltd | PHARMACEUTICAL PREPARATION FOR DIRECT COMPRESSION |
EP0890359B1 (en) * | 1996-02-29 | 2002-05-02 | Fujisawa Pharmaceutical Co., Ltd. | Tablets containing beta-lactam antibiotic and process for producing the same |
TWI225402B (en) | 1996-03-13 | 2004-12-21 | Biochemie Gmbh | Auxiliary-free agglomerates |
US5735891A (en) * | 1996-12-02 | 1998-04-07 | Sulzer Intermedics Inc. | Self-clamping anchoring sleeve |
WO2000025751A2 (en) * | 1998-10-30 | 2000-05-11 | Fuisz International Ltd. | Improved amoxycillin and clavulanate composition |
US7803402B2 (en) * | 2002-07-06 | 2010-09-28 | Sanjeev Khandelwal | Pharmaceutical preparations |
JP2007536378A (en) * | 2004-05-10 | 2007-12-13 | ルピン・リミテッド | New cefixime pharmaceutical formulation with enhanced bioavailability |
CN110041346B (en) * | 2019-04-17 | 2022-06-07 | 广东立国制药有限公司 | Low-cost preparation method of cefixime |
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AR208171A1 (en) * | 1972-09-29 | 1976-12-09 | Ciba Geigy Ag | PROCEDURE FOR OBTAINING NEW DERIVATIVES OF CEF-3-EM-4-CARBOXYL ACID |
US4708956A (en) * | 1985-12-12 | 1987-11-24 | Kyowa Hakko Kogyo Co., Ltd. | 3-position halogenated cephalosporin analogs and pharmaceutical compositions |
JPH01149728A (en) * | 1987-12-04 | 1989-06-12 | Fujisawa Pharmaceut Co Ltd | Antiulcerative agent |
JPH01242589A (en) * | 1988-03-22 | 1989-09-27 | Fujisawa Pharmaceut Co Ltd | Cephem compound |
IL94946A0 (en) * | 1989-07-13 | 1991-06-10 | Eisai Co Ltd | 3-substituted vinyl cephalosporin derivatives,their preparation and pharmaceutical compositions containing them |
-
1990
- 1990-11-15 FR FR9014210A patent/FR2669221B1/en not_active Expired - Fee Related
-
1991
- 1991-11-08 DE DE69104220T patent/DE69104220T2/en not_active Expired - Lifetime
- 1991-11-08 ES ES91920476T patent/ES2060417T3/en not_active Expired - Lifetime
- 1991-11-08 EP EP91920476A patent/EP0557389B1/en not_active Expired - Lifetime
- 1991-11-08 DK DK91920476.8T patent/DK0557389T3/en active
- 1991-11-08 JP JP50040992A patent/JP3253074B2/en not_active Expired - Fee Related
- 1991-11-08 AT AT91920476T patent/ATE111734T1/en not_active IP Right Cessation
- 1991-11-08 KR KR1019930701448A patent/KR100226386B1/en not_active IP Right Cessation
- 1991-11-08 CA CA002094122A patent/CA2094122C/en not_active Expired - Lifetime
- 1991-11-08 WO PCT/FR1991/000872 patent/WO1992008463A1/en active IP Right Grant
- 1991-11-08 US US08/064,049 patent/US5514383A/en not_active Expired - Fee Related
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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KR20030078105A (en) * | 2002-03-28 | 2003-10-08 | (주)다산메디켐 | The novel composition of excipient for solid dosage form |
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Publication number | Publication date |
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DE69104220T2 (en) | 1995-01-26 |
WO1992008463A1 (en) | 1992-05-29 |
CA2094122A1 (en) | 1992-05-16 |
KR930702004A (en) | 1993-09-08 |
ATE111734T1 (en) | 1994-10-15 |
EP0557389B1 (en) | 1994-09-21 |
ES2060417T3 (en) | 1994-11-16 |
EP0557389A1 (en) | 1993-09-01 |
JP3253074B2 (en) | 2002-02-04 |
US5514383A (en) | 1996-05-07 |
CA2094122C (en) | 2004-07-20 |
JPH06502420A (en) | 1994-03-17 |
DK0557389T3 (en) | 1994-10-17 |
DE69104220D1 (en) | 1994-10-27 |
FR2669221A1 (en) | 1992-05-22 |
FR2669221B1 (en) | 1993-01-15 |
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